Preparation of 9-oxo-13-trans-prostenoic acid esters by alanate addition to cyclopentenone

ABSTRACT

This disclosure describes a process for the preparation of homologues, analogues, congeners, and derivatives of 9-oxo-13trans-prostenoic acid which possess antimicrobial activity and prostaglandin-like hypotensive activity.

United States Patent 691% Bernady et al.

1 in Dec. 10, 1974 PREPARATION or a 9-OX01I3 TRANS-PROSTENOIC ACID ESTERS BY ALANATE ADDITION TO CYCLOPENTENONEI Assignee: American Cyanamid Company,

Stamford, Conn.

Filed: Apr. 30, 1973 v App]. No.: 355,844

Related US. Application Data Division of Ser. No. 162,71], July 14, 1971, abandoned. I

us. 01. 260/468 1), 260/2472 B, 260129115, 260/295 R, 260/3263, 260/340.9, 260/410, 260/410.9 R; 260/413, 260/448 A,

260/514 D, 260/514 K, 260/566 Ali,

activity..

[58] Field of Search 260/468 D, 514 D [56] References Cited OTHER PUBLlCATlONS Patai, The Chemistry of Carbonyl Compounds, pp. 671-679, (1966).

Fieser et al., Reagents for Organic Synthesis, Volume 2, 141-142, (1969).

Primary Examiner-Robert Gerstl Attorney, Agent, or Firm-Edward A. Conroy, Jr.

{57] ABSTRACT This disclosure describes a process for the preparation of homologues, analogues, congeners, and derivatives of 9 oxo-134rans-prostenoic acid which possess antimicrobial activity and prostaglandin-like hypotensive 10 Claims, No Drawings BRIEF SUMMARY OF THE INVENTION This invention relates to new organic compounds and, more particularly, is concerned with a class of compounds related to the natural prostaglandins. The novel compounds of the present invention may be represented by the following general formula:

R: ll wherein n is the integer 1 or 2; Y is a divalent radical selected from the group consisting of and o no H OH Z is a divalent radical selected from the group consisting of cis III II wherein m is an integer from I to 8, inclusive, p is an integer from 2 to 4, inclusive, 1; is an integer from 3 to 6, inclusive, and R is a lower alkyl group having up to three carbon atoms; R is selected from the group consisting of I a. a straight chain alkyl group having from three to carbon atoms,

b. a straight chain alkyl group having from two to six carbon atoms and having one branched methyl group,

0. a straight chain alkenyl group having from three to six carbon atoms,

d. a straight chain w-haloalkyl group having from three to six carbon atoms,

e. a straight chain w-mercaptoalkyl group having from three to six carbon atoms,

f. a straight chain w-carboxyalkyl group having from three to six carbon atoms, and

g. moieties of the formulae:

wherein p, q and R are as hereinabove defined, R is hydrogen or lower alkyl, R,-, is hydrogen or lower alkyl. and R and R taken together with the N(itrogen) is pyrrolidino, piperidino or morpholino;

and R is selected from the group consisting of hydroxy,

- alkoxy having from one to four carbon atoms, pyridoxy, 2,2,2-trichloroethoxy and a moiety of the formula:

wherein p, R, and R are as hereinabove defined. Suitable lower alkyl groups contemplated by the present invention are those having up to four carbon atoms such as, for example, methyl, ethyl, isopropyl, secbutyl, etc. Halo is exemplified by chloro, bromo or iodo whereas pyridoxy may be 01-, ,B-, or y-pyridoxy.

DETAILED DESCRIPTION OF THE lNVENTlON The prostaglandins are a family of closely related compounds which have been obtained from various animal tissues, and which stimulate smooth muscle, lower arterial blood pressure, antagonize epinephrineinduced mobilization of free fatty acids, and have other pharmacological and autopharmacological effects in mammals. See Bergstrom et al., J. Biol. Chem. 238, 3555 (1963) and Horton, Experientia 21, 113 (1965) and references cited therein. All of the so-called natural prostaglandins are derivatives of prostanoic acid:

on, un 013 cm CH, 014, 014, cm

ong cm CIR CI] CI:

Thy hydrogen atoms attached to C-8 and 012 are in wherein m and n are as hereinabove defined and X. is

iodo or bromo. v In accordance with this reaction scheme, the cycloalk-2-en-l-ones (VIII) are developed by first converting -2-carbethoxycyclopenta-none or 2-carbethoxycyclohexanone (l) to the sodium enolates thereof by means of sodium hydride in dimethoxyethane and then treating the sodium enolate with an ethylm-haloalkanoate (II). There is'thus obtain'ed the corresponding cloalkanone (III) which is then hydrolyzed and decafboxylated to afford the Z-(m-carboxyalkyl) 'cycloalkanone (IV). This acid is then esterified with ethanol whereby the 2-( m-carbethoxyalkyl)cycloalkanone (V) is obtained. The reaction conditions for carryingout the above sequence of reactions are well known in the art. Theconversion of the cycloalltanone (V) to the enol acetate (V!) is effected by heating with acetic anhydride in the presence of p-toluenesulfonic acid. Preparation of the enol acetate (VI) usually requires heating for a period of from about eight to thirty-six hours. During this period, it is preferable to allow by-product acetic acid to distill out in order to force the reaction to completion. The bromination of the enol acetates (VI) to the 2-bromocycloalkanones (VII) is preferably carried out in a two phase system as follows. A solution of bromine in chloroform is added to a rapidly stirred mixture of a solution of the enol acetate (VI) in chloroform and an aqueous solution of an acid acceptor such as calcium carbonate or soda ash. This addition is carried out at -5C. over a period of about half an hour, stirring is continued for an additional period of about half an hour to a few hours, and the product (VII) is then isolated by standard procedures. The dehydrobromination of the 2-bromocycloalkanones (VII) is 2-carbethoxy-2-( w-carbethoxyalkyncy preferably carried out in dimethylformamide with a (CH'DBH wherein X, n, q and R are as hereinabove defined.

The required cycloalk-2-en-l-one intermediates of general structure (XVI), wherein the side-chain has a lower alkyl group alpha to the carbethoxy function, may be prepared in accordance with the following re action scheme:

wherein n, I and R are as hereinabove defined. In accordance with this reaction shceme, the 2-(wcarbethoxyalkyl)cycloalk-Z-en-1-ones (IX) are converted to the corresponding l-methoximino-Z-(wcarbethoxyalkyl)-2-cycloalkenes (X) by treatment with methoxyamine. With the ring carbonyl function thus blocked it is possible to effect a preferential reduction of the ester group by treatment with diisobutylaluminum hydride. The resulting alcohol (XI) is converted to a tosylate derivative (XII), which undergoes displacement on treatment with the sodium salt of a diethyl lower alkyl malonate (XIII) to provide the disubstituted malonate derivatives (XIV). Hydrolysis and decarboxylation as well as concomittant cleavage of the methoximino blocking group provides the desired Z-(w-carboxy-a-lower alkyl-alkyUcycloalk-2- en-l-ones (XV), which are readily converted to the corresponding ester (XVI) by the usual Fisher procedure.

The requisite 2-(w-carbethoxy-B-oxa-alkyl)cycloalk- 2-en-l-ones (XXII) and 2-(w-carbethoxy-3-thiaalkyl)cycloalk-2-en-l-ones (XXVI) may be prepared inzaccordance'with the reaction schemes of Flowsheet C, wherein n and q are as hereinbefore defined.

In accordance with the reaction scheme shown in Flowsheet C, for the preparation of the oxa derivative (XXII), an appropriate 2 (w-carbethoxyaIkyI)cycloalk- 2-en-l-one (XVII) is converted to the corresponding methoxime (XVIII), the esterfunction of which is then preferentially reduced. with diisobutylaluminum hydride to afford the methoxime alcohol (XIX). The alcohol (XIX) is converted on;,treatment with n-butyl lithium to the lithio alcoholate, which. then is O- alkylated by reaction withethylbromoacetate to provide (XX). Hydrolysis with acetone-aqueous hydrochloric acid furnishes the deblocked keto-acid.(XXI),

which is then re-esterified with ethanol in the presence I of p-toluenesulfonic acid to give the required-Z-(wcarbethoxy-3-oxa-alkyl)cycIoaIk-Z-en-lone (XXII). O-Alkylation can also be accomplished by treatment of the lithio alcoholate of (XIX) withsodium or other metal salt of bromoacetic acid, in which case the free carboxylic acid corresponding to ester (XX) is obtained. Hydrolysis as for (XX) provides the keto acid (XXI). The preparation of the thia derivatives (XXVI), proceeds from the intermediate alcohol (XIX), which after conversion to the tosylate intermediate (XXIII) and reaction with the sodium salt-of ethyl mercaptoacetate furnishes intermediate (XXIV). Deblocking of XXIV with acetone-aqueous hydrochloric acid provides the keto-acid (XXV), which on re-esterifieation with ethanol the requires 2-(arcarbethoxy-3-thia-alkyl)cy- 7 (XXX) (XXI X) nonyne,

wherein Z is a divalent radical selected from the group consisting of -(CH 2)q a)2'- 2, 2)q-- 2 and (CH S-CH and n, m, q and R are as hereinbefore defined; R' is a lower alkyl group, preferably methyl or n-butyl; and R is a straight chain alkyl group having from three to 10 carbon atoms, a straight chain alkyl group having from two to six carbon atoms and having one branched methyl group, a straight chainalkenyl group having from four to six carbon atoms, or a straight chain w-chloroalkyl group having from three to six carbon atoms. The compounds (XXIX) are readily prepared by the conjugate 1,4-addition of an alanate salt (XXVIII) to a 2-substituted cycloalk-Z-enl-one (XXVll). The yields for this operationare usu ally high and a clean product, uncontaminated with l,2-addition product, is usually obtained. Furthermore, the transfer of the alkene group is effected with retention of the trans-configuration of the hydrogen atoms attached to the double bond, and no-reaction is noted at the earbethoxy function of (XXVII); Another noteworthy aspect of this reaction is that it does not require a catalyst. The alanate salts (XXVlll) are conveniently prepared by the reaction of an appropriate l-alkyne (RC CH) with diisobutylaluminum hydride, followed by reaction with a lower alkyl lithium derivative, preferably methyl lithium or n-butyl lithium. Suitable l-alkynes which may be thus employed are, for example, l-pentyne, l-hexyne, l-decyne, l-hendecyne, ldodecyne, 3-methyl-i-butyne, l-heptyne, l-octyne, l- 5-methyll -hexyne, .7methyll -octyne, 7- methyl- 1 -nonyne, 3-methyll -octyne, 4-methyll octyne, oct-S-en-l-yne, hept-Sen-l-yne, hex-4-enlyne, 5-chloro-l-pentyne, -chloro-l-hexyne, 7- chlorol -heptyne, 8-chlorol -octyne, etc. The reaction of the l-alkyne with diisobutylaluminum hydride cleanly provides the trans-double bond and is preferably carried out in an inert solvent such as benzene, toluene, and the like at temperatures in the range of 4060C. for several hours-The solvent is removed in vacuo and the subsequent reaction with methyl or nbutyl lithium is preferably carried out in an ether-type solventsuch as diethyl ether, dibutyl ether, tetrahydrofuran, and the like. This reaction is rapid and is preferably carried out at-l0C. with cooling. The conjugate 1,4-addition of the resulting alanate salt (XXVllI) to the cycloalk-Z-en-l-on (XXVll) is preferably carried out at ambient temperatures for a period of 12 to 24 hours. This reaction is also best carried out in an ethertype solvent such as diethyl ether, dibutyl ether, tetra-- hydrofuran, and the like. The intermediate alanateenolate adduct is then hydrolyzed in situ with dilute hydrochloric acid with cooling, and the products (XXlX) are isolated in the usual manner well known in the art. The conversion of the esters (XXIX) to the acids (XXX) is readily accomplished by mild saponification procedures such as in 0.5N aqueous-methanolic KOH at room temperature for 20-48 hours.

Other compounds of this invention may be prepared as illustrated by the following flowsheets In Flowsheet E, n, p, Z, R R and R have the values hereinbefore defined. I

(cum-K k (XXXV) Z-COzH (XLI) arming-LR,

(XXXIX) (XLII) In Flowsheet E, treatment of the chloro derivative (XXXI) with sodium iodide provides the iodo derivative (XXXII), which on treatment with the sodium salt of an alkyl mercaptan furnishes the thia derivative (XXXIII), saponification of which gives (XXXVI). Sulfur-oxidation of (XXXIIl) with an equivalent of sodium metaperiodate affords the sulfoxide ester (XXXIV), which on saponification gives the corresponding acid (XXXV).

When the iodo derivative v( XXXll) is treated with diethyl sodio malonate the triester (XXXVlI) results, which on saponification provides the corresponding triacid, heating of which in refluxing xylene causes decarboxylation of the substituted malonic acid to give the diacid (XXXVIII).

For some displacement reactions it is preferable to protect the ring ketone function in (XXXll). This can be accomplished by conversion to the ethylene ketal derivatives (XXXIX). Treatment of (XXXIX) with pyrrolidine gives the pyrrolidino derivative (XL), acid hydrolysis of the ketal blocking group then gives the keto-aminoacid (XLl). Treatment of iodo ketal (XXMX) with a metal alkoxide provides a mixture of the oxa derivative (XLll) and the diene (XLlll), separable by chromatography. Ketal hydrolysis with acetone and p-toluenesulfonic acid of these two ketal esters gives the corresponding keto ester (XLlV)' and (XLVI), respectively, saponification of which furnishes the keto acids (XLV) and (XLVll), respectively.

Additional transfonnations are illustrated in Flowsheet F, wherein n, q and Z are as hereinabove defined, R" is hydrogen or lower alkyl, R' is lower alkyl, and R and R taken together with the N(itrogen) is pyr-. rolidino, piperidino or morpholino.

- In accordance with- Flowsheet F treatment of the chloroketone (XLVlll) with sodium iodide in refluxing acetone produces the iodoketo ester (L), mild saponification of which provides the corresponding acid (IL). Treatment of the iodoketone ester with thiourea, followed by treatment of the intennediate thiuronium salt with an equivalent of alkali affords the mercapto ketoester (Ll), which on saponification gives the corresponding acid (Llll). Other transformations are preferably carried out after blocking the ring keto function as an ethylene ketal, thus the preparation of compound (LII). Reaction of ketal (LII) with potassium phthalimide in dimethylformamide (preferably at about 70C. for about two hours) furnishes the phthalimido ketal (LIV). Deblocking of (LIV) to the amino ketoacid (LVI) is accomplished by first treating with potassium hydroxide in aqueous methanol followed by heating at reflux for about 18 hours with aqueous hydrochloric acid. Substituted amino groups can be introduced by treating iodo ketal (LII) with various amines to give (LV) followed by ester and ketal hydrolysis to the amino ketoacids (LVII).

Additional transformations are illustrated in Flowsheet G, wherein n, p and q are asdefined hereinbefore. The group R has all the possibilities that R; is defined above as having with the following exceptions:

(e) a straight chain w-mercaptoalkyl group having from three to six carbon atoms, (f) a straight chain w-carboxyalkyl group having from three to six carbon atoms, (g) moieties of the formulae:

and the possibility of (d) a straight chain-haloalkyl group having from three to six carbon atoms is limited to an w-chloroalkyl group. The synthesis of those compounds of this invention embodying at the same time Z and the above exclusions for R can be accomplished by transformations of (LX) or (LXII) wherein R contains an m-chloroalkyl group in the manner described above in Flowsheets E and F.

in Flowsheet G, which follows, the ring carbonyl function of the Z-(carbethoxymethyi)cyclopentanone (LVIII) is blocked by conversion to the ketal (LIX).

. The ester function in (LIX) is then reduced to an aidehyde by treatment with diisobutylaluminium hydride. This reaction is preferably carried out by addition of one molecular equivalent of this reagent to a solution of ester (LIX) in hexane or other hydrocarbon solvent, cooled to 78C. After about 2.5 hours at this temperature the entire reaction mixture is poured quickly into aqueous excess mineral acid. and the product aldehyde (LXII) is obtaned upon immediate work-up in the usual way. The aldehyde (LXll) is then converted to (LX) by addition of (LXI!) to the ylid prepared from the (cu-carboxyalkyl) triphenyl phosphonium bromide-(LXI) and two molecular equivalents of sodium hydride in anhydrousdimethylsulfoxide. The use of dimethylsulfoxide by treatment with acetone and p-toluenesulfonic acid producing the keto acid (LXIII). Y

FLOWSI-IEET G i i I (CHQD C R I I (GHQn C 1'1 III I CH;IVCO2C2H5 CH2C02C:II5 0 0 0 (LVIII) (LIX) i ii (CHQn (CHZhr' i l i i CHr?=(I3(CH2) COzH CH2-CHO 0 o H H r o .0

(cis) (LX) (LXII) i (CHTXF'X 1 it I) cHz( J= J(oH2),-C0n2r (cis) (L XIII) The various 9 hydroxy derivatives of this invention are prepared by reduction of the corresponding 9-keto ester or by subsequent transformations of the reduction product of the type recorded in Flowsheets E and F. Saponification of the ester provides the corresponding 9- hydroxy acids. The reduction is preferably carried out in the usual manner with sodium borohydride in ethanol as a solvent.

The prostanoic acids of this invention are convertable to the corresponding ester by first treating with thionyl chloride and then reacting the resulting acid chloride with an appropriate alcohol in the presence of an' ins, distillation, or a combination of these. Purification of the compounds of this invention can be accomas a solvent for this reaction leads to the predominant formation of the desired cis double bond in product (LX). The ketal blocking group in (LX) is then cleaved plished by means known in the art for the purification of prostaglandins and lipids, fatty acids, and fatty esters. For example, reverse phase partition chromatogtion. Alternatively, the acid may be esterified with anoptically active alcohol, e.g., d or l-menthol, estradiol 3-acetate, etc., and the diastereoisomeric esters then resolved.

Resolution of the racemic prostaglandin-like compounds of this invention can also be accomplished by reverse phase and absorption chromatography on an optically active support and adsorbent and by selective transformation of one isomer with a biologically-active prostaglandin transfonning system. Such transformations can be carried out by incubation or perfusion using methods well established in the art, followed by isolation and recovery of the isomer resistant to the metabolic transformation applied.

Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the novel compounds of the present invention when R is hydroxy. The cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tri(lower alkyl)amine cations (e.g., triethylamine), procaine, and the like.

The novel compounds of the present invention are obtainable as yellow oils having characteristic absorption spectra. They are relatively soluble in common organic solvents such as ethanol, ethyl acetate, dimethylformamide, and the like. The cationic salts of the compounds when R is hydroxy are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively soluble in water, methanol, and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.

The novel compounds of the present invention are useful as hypotensive agents and their prostaglandinlike hypotensive activity was demonstrated in the following test procedure. This procedure is a modification of the technique described by Pike et al., Prostaglandins, Nobel Symposium 2, Stockholm, June, 1966; p. 165.

Male Wistar strain rats (Royal Hart Farms) averaging approximately 250 grams in weight were fastened to rat boards in a supine position by means of canvas vests and limb ties. The femoral area was infiltrated subcutaneously with lidocaine and the iliac artery and vein were exposed and cannulated. Arterial blood pressure (systolic/diastolic) was recorded using a Statham P Db pressure transducer-Offner dynograph system. To obtain a stable blood pressure, the animals were anesthetized before use with pentobarbitol, 3O mg-./kg. of body weight intravenously, and also were given hexamethonium bitartrate, 2 mg./kg. of body weight intravenously. The test compounds were prepared by ultrasonic dispersion in a saline-Tween 80 vehicle. A constant intravenous dose volume of 0.5 ml. was administered and test doses ranged from 0.1 to 10.0 mg./kg. of body weight. Increasing or decreasing doses were selected depending on the dose response obtained. In

Table I below are set forth the minimal doses required to produce a decrease of about 10 mm. in diastolic blood pressure for typical compounds of the present invention.

TABLE 1 Minimal Effective Dose Compound (mg/kg. of

body weight) ethyl 9-oxol 3-trans-prostenoate 0.5 ethyl 20-butyl-9-0xo-l3-trans-prostenoate l0 ethyl 20-chloro-9-oxol S-trans-prostenoate 0.5 ethyl 9-oxo-20-norl 3-trans-prostenoate 0.6 ethyl 20-methyl-9-oxol B-trans-prostenoate 0.5 et y l0 l 7-methyl-9-oxol 9,20-dinorl 3-tmns-prostenoate ethyl 0.2-l 20-chloro-9-oxol 7, l 8, l 9-trinorl 3-transprostenoate ethyl 9-oxol 3-transl 7-cis-prostadienoate 0.2-2 ethyl 8 9-oxo-3.4,5,6,7-pentanorl 3-trans-prostenoate ethyl 9-oxol Oa-homol 3-trans-prostenoate 2 ethyl 9oxo-l8-thia-lB-trans-prostenoate 2 ethyl 9-oxol 8-oxythial 3-trans-prostenoate g eth l 2OEO-dicarbethoxy-Q-oxol 8. l 9-dinorl 3-trans- 20-chloro-9-hydroxyl 7. l 8. l9-trinorl 3-trans- 2 prostenoic acid l7-methyl-9-hydroxy-19.20-dinor-l3-trans- 0.2-2

rostenoic acid -hydroxy-6,7-dinorl 3-trans-prostenoic acid 2 20-carboxy-9-oxol 8,19-dinorl 3-trans-prostenoic 8 acid l8-oxa-9-oxo-l3-trans-prostenoic acid 2 3- yridyl 9-oxo-l3-trans-prostenoate 0.4-4 n-Butyl 9-oxo-l3-transrostenoate 2 B-dimethylaminoethyl -oxol 3-trans-prostenoate 0.5-2 9-hydroxy-l3-transprostenoic acid 2 This hypotensive effect is short acting and a continuous infusion of compound is necessary to maintain the effect. Nevertheless, it is authoritatively claimed that hypotension induced by prostaglandins is of an ideal nature and therefore, despite the necessity of infusion, these compounds may be useful in the treatment of certain hypertensive crisis situations such as ecampsia. A description of this problem appears in The Medical Letter on Drugs and Therapeutics (p. 31-32, issue of April 3, 1970). Also, in a news item from Medical The novel compounds of the present invention are also useful as antimicrobial agents. They possess antibacterial and antifungal activity in vitro against a wide variety of standard laboratory microorganisms as determined by the agar-dilution streak-plate technique. In this assay, the compounds to be tested are made up to contain 2.5 mg. of test compound per milliliter of solution. Observing sterile techniques, twofold serial dilutions are made of each test solution. One milliliter of each of the original solutions and of each of the serial dilutions is then added to 9 ml. of warm sterile nutrient agar capable of supporting growth of the bacterial test cultures. A second set of agar dilutions is prepared identical to the first except that the nutrient agar is designed to support the growth of the fungal test cultures.

The standard sterile nutrient agar solutions containing the difierent dilutions of the test compounds, along with suitable and comparable control dilutions containing no test compound, are then allowed to cool in Petri dishes thereby forming solidified agar plates. The test bacteria and yeast-like fungi are prepared for use by growing in broth overnight. The spores of the filamentous fungi are harvested from mature agar slant cultures and are suspended in sterile physiological saline solution. A loopful of each of the resulting live suspensions is then, still employing sterile techniques, streaked upon the surfaces of each of the agar plates and the'resulting streaked plates are then incubated. After an appropriate period of time, each of the streaks on each of the plates is inspected visually and the extent, if any, of bacterial or fungal growth is noted. The minimal inhibitory concentration (expressed in micrograms per milliliter) is defined as the concentration of test compound causing complete inhibition of growth of any particular organism.

in a representative operation, and merely by way of illustration, the minimal inhibitory concentration of typical compounds of the present invention against a variety of test organisms as determined in the abovedescribed assay are set forth in Tables ll and ill below:

TABLE II Minimal inhibitory Compound conc. mc ml.

9-oxo-l3-transprostcnoic acid -50 50 SO 50 9-oxo-l8.19,20-trinor-U-trans-prostcnoic acid 250 250 250 cthyl 9-oxol 8 l 9,20-trinorl 3-trans-prostenoatc 250 cthyl 250 250 250 250 IS-methyl-Q-oxo-l 7,18 l 9,20-tetranorl 3-transrostcnoate O-butyl-9-oxol 3-trans-prostenoic acicd 250 ethyl ZO-butyI-Q-oxol 3-trans-prostcnoate 250 20-chloro-9-oxo-lJ-trans-prostenoic acid 250 62 16 62 ethyl 20-chloro-9-oxo-l3-transrostenoate 250 250 9-oxo-20-nor-l3-trans-prostenorc acid 50 50 25 20-mcthyl-9-oxo-lS-trans-prostenoic acid 100 25 25 l7 -(rjnethyl-9-oxo-l9,20-dinor-l3-trans-prostcnoic 5O 50 25 25 am 9-oxo-l0a-homo-l 3-trans-prostenoic acid I00 ct y 250 20 chloro-9-oxol 7, l 8, l 9-trinor-l B-transprosrcnoate 20;;hloro-9-oxol 7, l 8,19-trinor-l S-trans-prostenoic 250 250 250 250 am 9-oxo-6,7-dinor-l3-trans-prostenoic acid 250 250 250 250 9-hydr0xy-l3-trans-protenoic acid 50 25 5O 50 fi-dlmethylaminoethyl 9-oxo-l3-trans-prostenoate 250 250 ethyl 250 250 20-iodo-9-oxol 7,1 8, l 9-trinor-l 3-trans-prostcnoate 9-oxo-l8-thia-l3-trans-prostenic acid 250 125 ethyl 9-oxo-l8-oxythia-l B-trans-prostenoate 250 250 9-hydroxy6,7-dinor-lB-trans-prostenoic acid 250 62 62 62 l8-n xa-9-oxo-l3-trans-prostenoic acid 250 250 9-oxo-l3-trans-l7-cis-prostadienoic acid 125 62 62 62 20-chloro-9-hydroxyl 7, l 8, l 9-trinorl B-trans- 250 250 250 prostenoic acid l7-methyl-9-hydroxy-19,20-dinor-l3-trans- 62 62 62 prostenoic acid ethyl 9-oxo-3,4,5,6,7- entanor-l3-trans-prostenoate 250 125 ZO-mercapto-Q-oxo-l -trans-prostenoic acid 125 250 250 9oxo-3,4,5,6,7-pentanor-l3-trans-prostenoic acid 250 250 125 250 (l) Microsporum canis ATCC l02l4 (ztM rqsp wnsyp em .AICC 14683 (3) Trichophylon mnsunmr NIH 662 (4) Trichophymn memagrophyles E l l TABLE III 7 Minimal inhibitory Compound conc. mc ml.

9-oxo-l3-traris-prostenoic acid 250. 62 250 62 9-oxo-l8,l9,20-trinor-l3-trans-prostenoic acid 250 ethyl 9-oxol 8, l 9,20-trinorl 3-trans-prostenoate 250 e y y 250 62 lS-rncthyl-Q-oxo-17,18,19,20-tetranor-l3-transgrostenoate O-butyl-9-oxo-IB-trans-prostenoic acid l0 10 ethyl -20-butyl-9-oxol 3-trans-prostenoate Minimal inhibitory Compound 7 conc. mc .ml.

20-chloro-9-oxo-l3-trans-prostenoic acid 62 250 ethyl 20-chloro-9-oxo-l3-trans-prostenoate 250 250 ethyl 9-oxo-20-nor-l3-trans-prostenoate 62 9-oxo-20-nor-l3-trans-prostenoic acid 50 62 20-methyl-9-oxo-l3-trans-prostenoic acid 100 25 ethyl 62 l7-methyl-9-oxo-19,20-dinor-l3-trans-prostcnoate l 7-mcthyl-9-oxo-19,20-dinor-l3-trans-prostenoic 50 62 acid 9-oxo-l0a-homo-l3-trans-prostenoic acid 25 cthy 250 20-chloro-9-oxol 7. l 8, l 9-trinor-l 3-transprostenoate 'lQ-ghloro-Qcxol 7, l 8, l 9-trinorl 3-trans-prostenoic 250 3- yridyl 9-oxo-l3-trans-prostenoate 50 et yl 9-oxo-l8-thia-l3-trans-prostenoate 250 n-butyl 9-oxo-l3-trans-prostenoate 250 ethyl 9-oxo-6,7-dinorl 3-trans-prostenoate 250 9-oxo-6,7-dinor-l 3-trans-prostenoic acid 250 250 9-hydroxy-l3-trans-prostenoic acid 25 B-dimethylaminoethyl 9-oxol 3-trans-prostenoate l ethyl 9-hydroxy-l3-trans-prostenoate 25 eth l 62 -1odo-9-oxo-l7,18,19-lrinor-l3-trans-prostenoate ethyl 20-iodo-9-oxo-l3-trans-prostenoate 62 9-oxo-l8-thia-l3-trans-prostenoic acid 250 ethyl 250 20,20-dicarbethoxy-9-oxol 8, l 9-dinorl 3-transprostenoate ethyl 9-oxo-l8-oxythia-l3-trans-prostenoate 250 250 ethyl 9-hydroxy-6,7-dinor-l3-trans-prostenoate 6 9-hydroxy-6.7-dinor-l3-trans-prostenoic acid 250 62 9-oxo-l3-trans-cis-prostadienoic acid I 62 20-chloro-9-hydroxyl 7. l 8, l9-trinorl 3-transprostenoic acid l7-methyl-9-hydroxy-l9,20-dinor-l3-trans- 250 62 prostenoic acid ethyl 9-oxo-3,4.5 ,6,7-pentanorl 3-trans-prostenoate 125 20-mercapto-9-oxol 3-trans-prostenoic acid 125 9-oxo-3,4,5 ,6,7-pentanorl 3-trans-prostenoic acid 250 lOO I0 (5) Trit'lmplrvum ruhrum E 97 (6) MywbacIt-rium snn'gmalix ATCC 606 (7) Slapllylocmmx aureu: Rose ATCC l4l5 4 (2 Slreplmmcus mugmm C 203 Topical preparations containing the novel compounds of the present invention or cationic salts thereof when R is hydroxy, it is expected, will prove particularly useful. Such compositions would be de signed for administration to subjects exposed to, or infected with sensitive bacteria or fungi for either treatment or prophylaxis and may include ointments, creams, emulsions, unguents, salves, emollients, sprays, washes or the like. In addition, the compounds may be used in the form of solutions, suspensions, emulsions, washes, powders, dusts, mists, soaps, sprays, aerosols, drenches, or other forms for the purpose of cleaning, disinfecting, or sterilizing surgical instruments, laboratory glassware or instruments, hospital walls or other surfaces, linens, dishes, laboratory tables, coops, cages, or the like. Likewise these compounds might be incorporated into soaps, detergents, sprays, or the like in the home, farm, office 'or elsewhere with the purpose of preventing or minimizing infection or contamination with sensitive bacteria or fungi. Painting, spraying, immersion or other means of effecting contact may be applied.

The novel compounds of the present invention also possess activity as anti-inflammatory agents, fertility controlling agents, central nervous system regulatory agents, saltand water-retention regulatory agents, fat metabolic regulatory agents, serum cholesterollowering agents and as abortifacients, anticonvulsants, bronchodilators and gastric acid secretion inhibitors.

Certain of the novel compounds disclosed herein possess utility as intermediates for the novel compounds of the present invention.

in accordance with accepted convention, a oz-substitutent at the'9'-position is behind the plane of the paper whereas a ,B-substituent at the 9-position is in front of the plane of the paper. This is usually represented by a bond for an oz-substituent, a bond for a B-substituent, and a M bond where both are indicated. Thus, the 9-hydroxy derivatives may be variously represented as follows:

vH TQ The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 19 boxylate (mixed methyl and ethyl esters), 52.4 g. (1.248 moles) sodium hydride (57.2% in mineral oil) and 1.6 l. of dimethoxyethane, is added dropwise 309 g. (1.212 moles) of ethyl -iodovalerate. The reaction mixture is stirred and heated at a reflux for IS hours. 5

EXAMPLE 2 Preparation of 2-(4-carboxybutyl )cyclopentanl-one A stirred mixture of 274 g. of 2-carbalkoxyl(mixed methyl and ethyl esters)-2-(4-carbethoxybuty1)cyclopentan-l-one (Example 1), 600 ml. of hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately 1% hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are wshed with saline and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of anoil.

EXAM LE 3 v Preparation of 2-( 4-carbethoxybutyl )cyclopentan- 1 -one A stirred solution of 124 g. (0.673 mole) of 2-(4- carboxybutyDcyclopentan-l-one (Example 2), 800 ml.

of ethanol and 1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, dilute sodium bicarbonate solution and again with saline, dried over 40 magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. 106109C. (0.23 mm).

EXAMPLE 4 Preparation of 2-carbalkoxy( methyl] ethyl )-2-( 3-carbethoxypropyl cyclopentan- 1 -one In the manner described in Example 1, treatment of EXAMPLE 5 Preparation of 2-(3-carboxypropyl)cyclopentan-l-one In the manner described in Example 2, treatment of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(3- carbethoxypropyl)cyclopentan-l-one (Example 4) with a 20% hydrochloricacid and acetic acid mixture gives a yellow oil.

EXAMPLE 6 Preparation of 2-( 4-carbethoxypropyl )cyclopentan- 1 -one In the manner described in Example 3, treatment of I 2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluene-sulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93C. (0.10 mm).

EXAMPLE 7 Preparation of ethyl and methyl 2( -carbethoxyhexyl l -cyclopentanon-2-carboxy1ate In the manner described in Example 1, ethyl and methyl 2 -cyclopentanone carboxylate is reacted with ethyl 7-bromoheptanoate to furnish the subject product, b.p. 147C. (0.09 mm).

EXAMPLE 8 Preparation of 2-( -carboxyhexyl )cyclopentan- 1 -one in the manner described in Example 2, ethyl and methyl 2-( -carbethoxyhexyl 1 -cyclopentanone-2- carboxylate (Example 7) is hydrolyzed to furnish the subject product, b.p. 143C. (0.05 mm).

EXAMPLE 9 Preparation of 2-( -carbethoxyhexyl )cyclopentan- 1 -one in the manner described in Example 3,, 2-(6- carboxyhexyl )cyclopentan- 1 -one (Example 8) is esterified to furnish the subject product, b.p. C. (0.03 mm).

EXAMPLE 10 Preparation of ethyl (methyl) 7-( Z-carbethoxycyclohexanl -on-2-yl )heptanoate To a stirred suspension of 51 g. of sodium hydride (57% in mineral oil) in 675 ml. of dimethylformamide is added 200 g. of 2-cyc1ohexanone carboxylate (60% ethyl 40% methyl esters) over a 1-5 hr. period with external cooling to maintain the temperature at 2025C. The reaction mixture is stirred at ambient temperature for 15 minutes and heated to 50C. over 15 minutes. To the stirred mixture is added 300 g. of ethyl 7-bromoheptanoate .during a 10 minute period. The reaction mixture is stirred at 50-60C. for 4 hours, cooled, and poured into water. The product is obtained by ether extraction. The extract is washed successively with water and saturated sodium chloride, dried and evaporated to give a liquid which is purified by distillation, IR 1735 cm (ester carbonyls) and 1710 cm (ketone carbonyl).

EXAMPLE 1 1 Preparation of 7-(cyclohexan-1-on-2-y1)heptanoic acid A stirred mixture of 380 g. of mixed methyl and ethyl esters of 7-( Z-carbethoxycyclohexan- 1-on-2- yl)heptan0ate (Example 10), 202 ml. of concentrated sulfuric acid, 970 m1. of glacial acetic acid, and 970 ml. of water is refluxed for 22.5 hours. The cooled reaction mixture is treated with 380 g. of sodium carbonate and 2 liters of water and is extracted with ether. Acidic material is partitioned from the ether extract with 1.0M sodium carbonate. The aqueous phase is acidified with concentrated hydrochloric. acid and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated to give an oil.

EXAMPLE 12 Preparation of ethyl yl)heptanoate 7-(cyclohexanl -on-2- of 7-(cyclohexan-l-on-2- tract is washed with saturated sodium chloride, dried,

and evaporated. The product is purified by distillation to give a liquid, IR 1740 cm" (ester carbonyl) and 1715 cm (ketone carbonyl).

EXAMPLE 13 Preparation of 2-carbalkoxy(methyl-/ethyl)-2-( 3-carbethoxypropyl)- cyclohexan-l-one The subject compound is prepared in the manner described in Example by treatment of 2- cyclohexanone carboxylate (mixed methyl and ethyl esters) with sodium hydride and ethyl 4-iodobutyrate.

EXAMPLE l4 Preparation of 2-( 3-carbethoxypropyl )cyclohexan- 1 -one This compound is prepared from 2- carbalkoxy(methyl/-ethyl)-2-(3-carbethoxypropyl)cyclohexan-l-one (Example 13) by decarbalkoxylation according to the procedure described in Example 11 followed by esterification by the procedure of Example 12.

EXAMPLE 1s EXAMPLE l6 Preparation of 2-( 7-carbethoxyheptyl )cyclohexan- 1 -one Alkylation of 2-cyclohexanone carboxylate (mixed methyl and ethyl esters) with ethyl 8-bromoctanoate in accordance with the procedure of Example 10, followed by decarbalkoxylation by the procedure of Example l l and then esterification by the procedure of Example 12 is productive of the subject compound.

EXAMPLE l7 Preparation of 2-carbalkoxy(methyl/ethyl)-2-( carbethoxymethyl)- cyclopentan- 1 -one in the manner described in Example 1, treatment of cyclopentanone-2-carboxylate (mixed methyl and ethyl esters) with sodium hydride in dimethoxyethane followed by ethyl bromoacetate provides a yellow oil, b.p. l30-l3lC. (7 mm). Y

EXAMPLE 18 Preparation of Z-(carboxymethyl )cyclopentan- 1 -one In -the manner described in Example 2, the 2- carbalkoxy-2-carbethoxymethylcyclopentanone of Example 17 is decarbalkoxylated to provide 2- carboxymethylcyclopentan- 1 -one.

EXAMPLE 19 Preparation of 2-carbethoxymethylcyclopentan- 1 -one in the manner of Example 3, 2-(carboxymethyl)cyclopentan-l-one (Example 18) is esterified to provide the subject ester.

EXAMPLE 20 Preparation of l-acetoxy-2-( -carbethoxyhexyl )cyclopentl ene A stirred solution of g. of 2-(6-carbethoxyhexyl)- cyclopentan- 1 -one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at l 18C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml. The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution,

dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. l 18C. (0.07 mm).

EXAMPLE 21 Preparation of l-acetoxy-2-( carbethoxymethyl )cyclopentl -ene In the manner described in Example 20, treatment of 2-(carbethoxymethyDcyclopentan-l-one (Example 19) with acetic anhydride and ptoluenesulfonic acid monohydrate gives an oil, b.p. l3013lC. (7 mm).

EXAMPLE 22 Preparation of l -acetoxy-2-( 3-carbethoxypropyl )cyclopentl -ene Preparation of l -acetoxy-2-(4-carbethoxybutyl )cyclopentl -ene In the manner described in Example 20, treatment of 2-( 4-carbethoxybutyl )cyclopentan- 1 -one (Example 3 with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. l09l 10C. (037 mm)- EXAMPLE 24 Preparation of ethyl v 7-( l-acetoxycyclohexl -en-2-yl )heptanoate EXAMPLE 25 Preparation of v l-acetoxy-2-(3-carbethoxypropyl )cyclohexl -ene Treatment of 2-(3-carbethoxypropyl)cyclohexanl-one (Example 14) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.

EXAMPLE 26 Preparation of l-acetoxy-2-( S-carbethoxypentyl )cyclohexl-ene Treatment of 2-(S-carbethoxypentyl)cyclohexanl-one (Example 15) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.

EXAMPLE 27 Preparation of l -acetoxy-2-(7-carbethoxyheptyl )cyclohexl -ene Treatment of 2-(7-carbethoxyheptyl)cyclohexanl -one (Example 16) with acetic anhydrideby the procedure of Example 24 is productive of the subject compound.

EXAMPLE 28 Preparation of 2-( 6-carbethoxyhexyl )cyclopent- 2-en- 1 -one To a rapidly stirred mixture of 50 g. of l-acetoxy-2- (-carbethoxyhexyl)cyclopent-l-ene (Example 20) in 150 ml. of chloroform, 200 ml. of water and 18.8 g of calcium carbonate, cooled in an ice bath, is added dropwise over a period of about 30 minutes, a solution of 30 g. of bromine in 50 ml. of carbon tetrachloride. After stirring for an additional 45 minutes the chloroform layer is separated and washed successively with dilute sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure.

The residual oil is dissolved in 50 ml. of N,NN,N-dimethylformamide and added to a mixture of 33 g. of lithium bromide and 32 g. of lithium carbonate in 375 ml. of N,N-dimethylfonnamide, previously dried by refluxing with 375 ml. of benzene under a Dean-Stark apparatus followed by distillation of the benzene. The mixture is stirred at the reflux temperature for 30 minutes, then cooled and poured into 850 ml. of ice-cold water. The resulting mixture is acidified (cautiously) with 4N hydrochloric acid and extracted with ether three times. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure to afford 41.5 g of an amber oil. In order to convert any isomeric material to the desired product, 4L5 g. of the above material is treated with 0.500 g. of p-toluenesulfonic acid monohydrate in 450 ml. of absolute alcohol at the reflux temperature for 18 hours. The solution is taken to dryness under reduced pressure. The resulting gum is dissolved in ether and .washed with saturated sodium bicarbonate solution,

saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure. The residual oil is distilled to give 30.2 g. of product; b.p. 118C. (0.05 mm); h 229 my. (69950); k 5.75, 5.85, 6.15, 8.45 t; vapor phase chromatography shows 99% product, containing 1 2-( o-carbethoxyhexyl )cyclopentan- 1 -one.

This product can be purified by the following procedure. A mixture of 120 g. of 2-(6-carbethoxyheXyl)-2- cyclopentenone, containing approximately 5% of the saturated analogue, and 7.67 g. (10 mole percent) of p-carboxyphenylhydrazine in 400 ml. of absolute ethanol is stirred at ambient temperatures for 18 hours and is then refluxed for 1 hours. The mixture is cooled, the solvent is evaporated, and the residue is taken up into ml. of chloroform andpassed through a column of 450 g. of aluminum oxide (Merck). The filtrate is evaporated to yield a colorless oil containing 0.5% of the saturated impurity.

EXAMPLE 29 Preparation of Z-(carbethoxymethyl )cyclopent-Z-en- 1 -one In the manner described in Example 28, treatment of l -acetoxy-2-( carbethoxymethyl)cyclopentl -ene (Example '2l) with bromine and subsequent dehydrobromination with lithium bromide-lithium carbonate in N,N-dimethylformamide gives an amber oil. This material is subjected to chromatography on diatomaceous earth using an n-heptanezmethyl cellosolve system. Removal of the solvent from hold back volume 4.5-4.7 gives an oil which is then further treated with hydroxylamine hydrochloride, sodium acetate in ethanol at room temperature for 18 hours to give the desired product; b.p. 71C. (0.12 mm); M 222 p. (10,300); M 5.75, 5.85, 6.15, 8.65 1.

EXAMPLE 30 Preparation of i 2-( 3-carbethoxypropyl )cyclopent-Z-en- 1 -one In the manner described in Example 28, bromination of l -acetoxy-2-( 3-carbethoxypropyl )cyclopentl -ene (Example 22) followed by dehydrobromination with lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 3i Preparation of 2-(4-carbethoxybutyl )cyclopent-2-enl-one in the manner described in Example 28, treatment of l -acetoxy-2-( 4-carbethoxybutyl )cyclopentl -ene (Example 23) with bromine and subsequent treatment of the brominated product with a mixture of lithium bromide and lithium carbonate in N,N-dimethylforrnamide is productive of the subject compound. Treatment of this product with p-carboxyphenylhydrazine by the EXAMPLE 32 Preparation of l-methoximino-2-( o-carbethoxyhexyl )-2-cyclopentene To a mixture of 35.97 g. (0.151 mole) of 2-(6- carbethoxyhexyl)-2-cyclopentenone (Example 28) and 15.0 g. (0.180 mole) of methoxyamine hydrochloride in 300 ml. of absolute ethanol is added 25 ml. of pyridine and the resulting solution is stirred for 20 hours at ambient temperatures. The solvent is evaporated and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na SO and the solvent is evaporated to yield an oil. Distillation yields 38.7 g. of a colorless oil, b.p. l15-ll8C. (0.075 mm). IR (film): 1740, 1627, 1053, 890 cm. A (MeOH) 243 (13,000). NMR8(CDCl 3.89.

EXAMPLE 33 Preparation of l-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene To an ice cooled solution of 34.10 g. (0.128 mole of l-methoximino-2-(o-carbethoxyhexyl)-2-cyclopentene (Example 32) in 200 ml. of benzene under nitrogenv is added dropwise 225 ml. of a 25% solution of diisobutyl aluminum hydride in hexane. The resulting solution is stirred for 2 hours at -5C., poured onto ice and dilute hydrochloric acid, and the aqueous phase is saturated with sodium chloride. The organic phase is separated, washed with saturated brine, dried (Na SO and evaporated to yield an oil. The latter is dissolved in 100 ml. of hot hexane and cooled to yield 24.3 g. of crystals, m.p. 62-64C. IR (KBr) 3260, 1630, 1059, 893 cm. k 243 (14,200). NMR (CDCl )8: 2.37.

EXAMPLE 34 Preparation of l-methoximino-2-(7-p-toluenesulfonyloxyheptyl)-2- cyclopentene To a solution of 5.00 g. (0.0222 mole) of lmethoximino-2-(7-hydroxyheptyl)-2-cyclopentene (Example 33) in 50 ml. of dry pyridine at 0C. is added 8.45 g. (0.0444 mole) of p-toluenesulfonyl chloride and the resulting solution is chilled at 50C. overnight. The mixture is partitioned between 300 ml. of ice water and diethyl ether. The organic phase is washed with 1:1 ice cold hydrochloric acid, cold water, and cold saturated brine, dried (NaSOJK CO and evaporated under reduced pressure at room temperature to yield an oil. The latter is dissolved in 600 ml. of hexane, treated with 0.5 g. of Darco, filtered and evaporated to yield 7.7 g. of a colorless oil. IR (film) 1600, 1192, 1182, 1053, 890 cm. A (MeOH) 228 and 243.

EXAMPLE 35 Preparation of l -methoximino-2-( 8 ,S-dicarbethoxyoctyl 2cyclopentene To an alcoholic solution of sodiodiethyl malonate, prepared from 0.847 g. (0.036 g. atoms) of sodium, 100 ml. of absolute ethanol, and 7.05 g. (0.0440 mole) of diethyl malonate is added 7.7 g. of the tosylate of Example 34 and the mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (Naand evaporated to yield an oil. The excess diethyl malonate is distilled off under reduced pressure to yield 6.47 g. of a yellowish oil. 1R (film) 1755, 1728, 1625, 1054, 890 cm.

EXAMPLE 36 Preparation of l-methoximino-2-( 8 ,8-dicarboxyoctyl )-2- cyclopentene EXAMPLE 37 Preparation of l-methoximino-2-( 8-carboxyoctyl )-2-cyclopentene A solution of 3.926 g. (0.0126 mole) of the diacid of Example 36 in 20 ml. of xylene is refluxed for 1.5

hours, cooled, and evaporated'to yield a tan solid. IR (KBr) 1720, 1618, 1179, 1050, 986 cm.

EXAMPLE 38 Preparation of 2-( 8-carboxyoctyl )cycopent-2-enl-one The acid methoxime from Example 37 is refluxed for 5 hours with 55 ml. of acetone and 20 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na SO and evaporated to yield a tan solid. IR (KBr) 1745, 1665 cm. A (MeOH) 228 (12,600).

EXAMPLE 39 Preparation of 2-( 8-carbethoxyoctyl )cyclopent-2-en- 1 -one The acid ketone from Example 38 is Fisher esterified with ml. of absolute ethanol, 100 ml. of benzene,

and 20 mg. of p-toluenesulfonie acid for 6 hours,-

cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1 benzene-ether and the solution is passed through a column of 100 g. of Florisil. The filtrate is evaporated and the residue is distilled to yield 2.97 g. of a colorless oil, b.p. 137-l39C. (0.05 Torr).

EXAMPLE .40

Preparation of ethyl 7-(cyclohex-2-enl -one-2-yl )heptanoate To a stirred solution of ethyl 7-( l-acetoxycyclohex- 1-en-2-yl)heptanoate (Example 24) in 750 ml. of acetic acid and ml. of pyridine at 10C. is added a solution of 13.8 g. of bromine in 200 ml. of acetic acid over 20 minutes. The resulting solution is allowed to stand at ambient temperature for 45 minutes and is then decolorized with sodium sultite. The solution is poured into 800 ml. of half-saturated sodium chloride and extracted with 1:1 hexane-ether. The extract is washed successively with water and saturated sodium chloride, dried over sodium carbonate, and evaporated to give 32 g. of the crude bromoketone. To a stirred suspension of 14.2 g. of lithium bromide and 16.6 g. of lithium carbonate in 250 ml. of anhydrous dimethylformamide at 80C. is added the above bromoketone. The stirred mixture is heated to boiling over minutes and refluxed for 15 minutes. The cooled mixture is poured into 1000 ml. of water, acidified with dilute hydrochloric acid, and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated. The product is puritied by distillation to give a liquid, IR 1740 cm (ester carbonyl), 1685 cm (ketone carbonyl), and 1650 cm (olefin); NMR (CC11,) 6.63 (multiplet, vinyl proton).

EXAMPLE 41 Preparation of 2-( 3-carbethoxypropyl )cyclohex-Z-en- 1 -one In accordance with the procedure of Example 40, bromination of 1 -acetoxy-2-( 3-carbethoxypropyl )cyclohex-l-ene (Example followed by treatment with lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 42 Preparation of 2-( S-carbethoxypentyl )cyclohex-Z-enl-one By the procedure of Example 40, bromination of lacetoxy-2-( S-carbethoxypentyl )cyclohexl -ene Example 26) followed by treatment with lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 43 Preparation of 2-( 7-carbethoxyheptyl )cyclohexl -en-2-one By the procedure of Example 40, bromination of lacetoxy-2-( 7-carbethoxyheptyl )cyclohexl-ene (Example 27) followed by treatment with lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 44 y I Preparation of ethyl 9-oxo-l3-trans-prostenoate A solution of 1.102 g. of l-octyne in 2 ml. of benzene is treated with l 1.5 m1. of 15% diisobutylaluminum hydride in toluene and the solution is heated to 50C. for 2 hours. The solution is cooled, its solvent is removed in vacuo, and the resultingoil is treated with 5.45 ml.

- of 5.10% methyl lithium in diethyl ether with ice cool- (trans vinyl group); NMR (CDCl )85.14-5.87 (multiplet, 2H, vinyl protons, .l trans 15 Hz); Mass Spectrum, parent peak at 350 mp.

EXAMPLE 45 Preparation of ethyl 20-butyl-9-oxo-l 3-trans-prostenoate In the manner described in Example 44, 2-(6- carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from l-dodecyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls) 967 cm (trans vinyl group).

EXAMPLE 46 Preparation of ethyl 9-oxo- 1 8, l 9,20-trinorl 3-trans-prostenoate 1n the manner described in Example 44, 2-(6- carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from l-pentyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by distillation to give a liquid, IR 1740 cm (ester and ketone carbonyl) 967 cm" (trans vinyl group).

EXAMPLE 47 Preparation of ethyl l 5-methyl-9-oxo- 1 7, 1 8, l 9,20-tetranorl 3-transprostenoate EXAMPLE 48 Preparation of ethyl 20-chloro-9-oxo-1 3-trans-prostenoate 1n the manner described in Example 44, 2-(6- carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from S-chloro-l-octyne (W. J. Gensler and G. R. Thomas, J. Amer. Chem.

Soc., 73, 4601 (1951)], diisobutylaluminum hydride,

and methyl lithium. The crude product obtained by acid hydrolysis is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans vinyl group).

EXAMPLE 49 Preparation of ethyl 9-oxo-20-norl 3-trans-prostenoate A solution of 5.30 g. of l-heptyne in 10 ml. of benzene is treated with 40 m1. of 1.2N diisobutylaluminum hydride in hexane and heated at 50C. for 2 hours. The solution is cooled in an ice bath and diluted with 25 ml. of ether. To the solution is added 30 ml. of 1.6M nbutyl lithium in hexane. After stirring for 20 minutes at l5-25C. the resulting solution'is treated with a solution of 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 28). The mixture is stirred at 25C. for I8-20 hours and the product then is hydrolyzed with a mix ture of ice and hydrochloric acid. The crude product, obtained from the organic phase, is purified by chromatography on silica gel to give an oil, IR 1740 cm (ester and ketone carbonyls) and 967 cm (trans vinyl group).

EXAMPLE 50 Preparation of ethyl 20-methyl- 9-oxol 3-trans-prostenoate In the manner described in Example 49, 2-(6- carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from l-nonyne, diisobutylaluminum hydride and n-butyl lithium. The crude product obtained by acid hydrolysis and evaporation of organic solvent is purified by chromatography on silica gel to give an oil, IR 1740 cm (ester and ketone carbonyls) and 967 cm (trans vinyl group).

EXAMPLE 51 Preparation of ethyl 1 7-methyl-9oxo- 19,20-dinorl 3-trans-prostenoate In the manner described in Example 49, 2-(6- carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from S-methyl-lhexyne, diisobutylaluminum hydride and n-butyl lithium. The crude product obtained by acid hydrolysis and evaporation of the organic solvent is purified by chromatography on silica gel to give an oil, IR 1740 cm (ester and ketone carbonyls) and 967 cm trans vinyl group).

EXAMPLE 52 Preparation of ethyl 20-chloro-9-oxo-l7,1 8, 19-trinor- 1 3-tra'ns-prostenoate In the manner described in Example 49, 2'-(6- carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from 5 -chloro-lpentyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by distillation to give an oil, IR 1740 cm (ester and ketone carbonyls) and 967 cm (trans vinyl group).

EXAMPLE 53 Preparation of ethyl 9-oxo-1 3-propyl-l 8, 1 9,20 -trinor- 1 3-trans-prostenoate carbonyls); NMR (CCl.,) 8 5.2 ppm (multiplet, vinyl proton and a second oil (ethyl 9-oxo-17,18,19,20-tetranorprostanoate), IR 1740 cm (ester and ketone carbonyls); NMR (CCl.,) 8 1.0 ppm (multiplet, terminal methyl group).

EXAMPLE 54 Preparation of cis-S-octenl -yne A 57% sodium hydride dispersion (9.66 g., 0.23 mole) is washed free of mineral oil in a nitrogen atmosphere with hexane. The hydride is heated at C. with 220 ml. of dimethylsulfoxide for 45 minutes. The resulting green solution is cooled to 18C. and treated with a solution of 4-pentynyl-triphenylphosphonium iodide g., 0.22 mole) in 220 ml. of dimethylsulfoxide over a 25 minute period. The resulting red solution is stirred at ambient temperature for 45 minutes. To the solution is added a solution of freshly distilled propionaldehyde (14.0 g., 0.24 mole) in 10 ml. of di methylsulfoxide over a 10 minute period at 25C. After standing at room temperature, the reaction is quenched with half-saturated brine and brought to pH 4 with 4N HCl. The product is extracted with an ether-hexane mixture, and the extract is washed successively with water and brine, dried over MgSO and concentrated. The crude product is fractionated with a spinning band column to give a colorless distillate, b.p. 121-122C., IR 3270, 2110 and 1645 cm.

EXAMPLE 55 Preparation of ethyl 9-oxo-1 3-transl 7-cis-prostadienoate In the manner described in Example 49, 2-(6- carbethoxyhexyl)-2-cyclopentenone (Example 28) is added to the reagent prepared from cis-5-octen-1-yne (Example 54), diisobutylaluminum hydride, and nbutyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by distillation to give an oil, IR 740 cm (ester and ketone carbonyls) and 967 cm (trans-vinyl group).

EXAMPLE 56 Preparation of ethyl 9-oxo-6,7-dinor-1 3-trans-prostenoate In the manner described in Example 44, 2-(4- carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from l-octyne, diisobutylaluminum hydride, and methyl lithium. The product is obtained by acid hydrolysis, ether extraction and distillation to yield a colorless oil, b.p. l49l50C. (0.075 mm). IR 1740 cm (ester and ketone carbonyls) 963 cm (trans-vinyl group).

EXAMPLE 57 Preparation of ethyl 20 chloro-9-oxo-6,7-dinor- 1 3-trans prostenoat'e In the manner described in Example 49, 2-(4- carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from 8-chlorol -octyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product obtaianed by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls) 967 cm (trans-vinyl group).

EXAMPLE 58 PREPARATION OF ETHYL 9-oxo-6,7,20-trinorl 3-trans-prostenoate In the manner described in Example 44, 2(6- carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from l-heptyne, diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by sililca gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls) 967 cm (transvinyl group).

EXAMPLE 59 Preparation of ethyl 9-oxo-6,7-dinor-1 3-transl 7-cis-prostadienoate In the manner described in Example 55, 2-(4- carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from cis-S-octen-I-yne (Example 54), diisobutylaluminum hydride, and nbutyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls) 967 cm- (trans-vinyl group).

EXAMPLE 60 Preparation of ethyl 20-chloro-9-oxo-6,7, 1 7, 1 8, I 9-pentanorl I l-transprostenoate EXAMPLE 61 I Preparation. of ethyl 1 7-methyl-9-oxo6,7, 1 9,20-tetranorl 3-transprostenoate In the manner described in Example 49, 2-(4- carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from S-methyl-lhexyne, diisobutylaluminum hydride and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 62 Preparation of ethyl 9-oxo- 1 3-propyl-6,7 ,18 ,19,20-pentanorl 3-transprostenoate In the manner described in Example 44, 2-(4- carbethoxybutyl)-2-cyclopentenone (Example 31) is added to the reagent prepared from 4-octyne diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls).

EXAMPLE 63 Preparation of ethyl 9-oxo-3 ,4,5 ,6,7-pentanorl 3-trans-prostenoate In the manner described in Example 44, 2- (carbethoxymethyl)-2-cyclopentenone (Example 29) is added to the reagent prepared from l-octyne, diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 64 Preparation of ethyl 9-oxo-3,4,5 ,6,7-pentanorl 3-transl 7-cisprosotadienoate In the manner described in Example 55, 2- (carbethoxymethyl)-2-cyclopentenone (Example 29) is added to the reagent prepared from cis-S-octen-lyne (Example 54), diisobutylaluminum hydride, and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 65 Preparation of ethyl 20-chloro-9-oxo-3,4,5 ,6,7, l 7, l 8,19-octanor-l3-transprostenoate In the manner described in Example 49, 2- (carbethoxymethyl)-2-cyclopentenone (Example 29) is added to the reagent prepared from S-chloro-lpentyne diisobutylaluminum hydride, and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 66.

Preparation of ethyl 9-oxo-5 ,6,7-trinorl3-trans-prostenoate In the manner described in Example 44, 2-(3- carbethoxypropyl)-2-cyclopentenone (Example 30) is added to the reagent prepared from l-octyne diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gelchromatograhy to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 67 Preparation of ethyl 9-oxo-20-propyl-5,6,7-trinor- 1 3-trans-prostenoate In the manner described in Example 44, 2-(3- carbethoxypropyl)-2-cyclopentenone (Example 30) is added to the reagent prepared from l-undecyne, diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give aan oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 68 Preparation of ethyl 9-oxo-5 ,6,7, l 8, 1 9,20-hexanorl 3-trans-prostenoate In the manner described in Example 44, 2-( 3- carbethoxypropyl)-2-cyclopentenone (Example 30) is added to the reagent prepared from l-pentyne, diisobutylaluminum hydride and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm- (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 69 Preparation of ethyl 20-chloro-9-oxo-5 ,6,7-trinorl 3-transprostenoate In the manner described in Example 44, 2-(3- carbethoxypropyl)-2-cyclopentenone (Example 30) is added to the reagent prepared from 8-chlorol -octyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm(ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 70 Preparation of ethyl 9-oxo-7a,7b-bis-homo- I 3-trans-prostenoate In the manner described in Example 44, 2-(8- carbethoxyoctyl)-2-cyclopentenone (Example 39) is added to the reagent prepared from l-octyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 71 Preparation of ethyl 20-chloro-9-oxo-7a,7bis-homol 7, l 8, l 9-trinor- I 3- trans-prostenoate In the manner described in Example 49, 2-(8- carbethoxyoctyl)-2cyclopentenone (Example 39) is added to the reagent prepared from 5-chloro-lpentyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 72 Preparation of ethyl ZO-butyl-9-oxo'7a,7b-bis-homol 3-trans-prostenoate In the manner described in Example 44, 2-( 8- carbethoxyoctyl)-2-cyclopentenone (Example 39) is added to the reagent prepared from l-dodecyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm (trans-vinyl group).

EXAMPLE 73 Preparation of ethyl I 5-methyl-9-oxo-7a,7b-bis-homol 7, 18,19,20- tetranorl 3-trans-prostenoate In the manner described in Example 44, 2-(8- carbethoxyoctyl)-2-cyclopentenone (Example 39) is added to the reagent prepared from 3-methyll -butyne, diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis and ether extraction is purified by silica gel chromatography to give an oil, IR 1740 cm (ester and ketone carbonyls), 967 cm" (trans-vinyl group).

EXAMPLE 74 Preparation of ethyl 9-oxo- IOa-homo-l 3trans-prostenoate In the manner described in Example 49, 2-(6- carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from l-octyne, diisobutylaluminum hydride and n-butyl lithium. The

crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR I740 cm (ester carbonyl), I750 cm (ketone carbonyl), and 967 cm (transvinyl group).

EXAMPLE 75 Preparation of ethyl 20-butyl-9-oxo- 1 Oa-homol 3-trans-prostenoate In the manner described in Example 49, 2-(6- carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from l-dodecyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm(ester carbonyl), 1750 cm (ketone carbonyl) and 967 cm (trans-vinyl group).

EXAMPLE 76 Preparation of ethyl 20-chloro-9-oxol Oa-homol 3-trans-prostenoate In the manner described in Example 49, 2-(6- carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from 8-chloro-l-octyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm (ester carbonyl), 1750 cm" (ketone carbonyl), and 967 cm (trans-vinyl group).

EXAMPLE 77 Preparation of ethyl 20-chloro-9-oxol 7, I 8, l9-trinor-l0a-homo-l 3-transprostenoate In the manner described in Example 49, 2-(6- carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from S-chloro-lpentyne, diisobutylaluminum hydride, and n-butyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm (ester carbonyl), 1750 cm (ketone carbonyl), and 967 cm (trans-vinyl group).

EXAMPLE 78 Preparation of ethyl 9-oxo- 1 8, l 9,20-trinorl Oa-homol 3-trans-prostenoate 3,853,9 1 I 1 EXAMPLE 79 1 Preparation of ethyl 9-oxo- 1 Oa-homol 3-transl 7-cis-prostadienoate In the manner described in Example 49, 2-(6- carbethoxyhexyl)-2-cyclohexenone (Example 40) is added to the reagent prepared from cis-5-octen-l-yne (Example 54), diisobutylaluminum hydride, and nbutyl lithium. The crude product, obtained by acid by drolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm (ester carbonyl), 1750 cm (ketone carbonyl), and 967 cm (trans-vinyl group).

appropriate EXAMPLES -92 1 -alkyne the Table),

TABLE IV Example Cyclohexenone l-Alkyne Product 80 2-(3-carbethoxyprol-octyne ethyl 9-oxo-5,6,7-

pyl )-2-cyclohexetrinor- 1 0a hon1ol 3- none (Example 41) trans-prostenoate 8| 2-(3-carbethoxyprol-heptyne ethyl 9-0xo-5,6,7,-

pyl )-2-eyclohexe- ZO-tetranorl 0anone (Example 4i) homo-l3-transprost'enoate 82 2-(3-carbethoxypro 5-chloro-lethyl 20-chloro-9- pyl )-2-cyclohexepentyne oxol Oa-homo-S ,6.- none (Example 4i) 7, l7,l8,l9-hexanorl 3-trans-prostenoate 83 2-(3-carbethoxypro- B-methylethyl l5-methyl-9- pyl )-2-cyclohexel-butyne oxo-S ,6,7,l7,18 none (Example 41) l9,20-heptanor-l0a homol 3-transprostenoate 84 2-(5-carbethoxypenl-octyne ethyl 9-oxo7-nortyl )-2-cyclohexclOa-homol 3-transnone prostenoate mple 85 2(5-carbethoxypenl-undecyne ethyl 9-oxo-20-protyl )-2-cyclohexepl3y-7-norl Oa-homonone (Example 42) l -trans-prrostenoate 86 2-( 5-carbethoxypen- S-methylethyl l7-methyl-9- tyl)-2-c clohexel-hexyne oxo7,l9,20-trinornone xample 42) l0a-homo-l3-transprostenoate 87 2-(5-carbethoxypen- S-chloroethyl 20-chl0ro-9- tyl)-2-c clohexel-octyne oxo-l0a-homo-7- none xample 42) norl3-trans-prostenoate 88 2-(7-carbethoxyhepl-octyne ethyl 9-oxo-7a.l0a-

tyl )-2-cyclohexcbis-homol 3-transnone (Example 43) prostenoate 89 2-(7-carbethoxyhepl-hexyne ethyl 9-oxo-l9,20-

tyl )-2-cyclohcxediner-7a, l Oa-bisnone (Example 43) homo-l3-trans-prostenoate 90 2-(7-carhethoxyhep- 5-chloroethyl 20-chloro-9 none xample 43) homo-l7,l8,l9-trinor- 1 3-transprostenoate 91 2-(7-carbethoxyhep- 8-chloroethyl ZO-chloro-Q- tyl )-2-cyclohexel-octyne oxo-7a, IOa-blsnone (Example 43) homo-lS-transprostenoate 92 2(7-carbethoxyhep 4-octyne tyl)-2-c clohexenone xamplc 43) ethyl l3- r0 yl-9- oxol 8. l 8,28-trinor-7a, l (la-bishomol S-transprostenoate EXAMPLE 93 Preparation of ethyl 9-oxo-5,6,7-trinorl Oa-homol 3-transl 7-cisprostadienoate In the manner described in Example 49, 2-(3- carbethoxypropyl)-2-cyclohexenone (Example 41) is added to the reagent prepared from cis-S-octen-l-yne (Example 54), diisobutylaluminium hydride, and nbutyl lithium. The crude product, obtained by acid hydrolysis and evaporation of the organic solvent, is purified by chromatography on silica gel and distillation to give an oil, IR 1740 cm (ester carbonyl), l750 cm (ketone carbonyl), and 967 cm (trans vinyl group).

EXAMPLE 94 Preparation of ethyl 9-oxo-7a, lOa-bis-homol 3-transl 7-cis-prostadienoate EXAMPLE 95 Preparation of ethyl 20-iodo-9-oxol 7, l 8, l9-trinorl3-trans-prostenoate EXAMPLE 96 Preparation of ethyl 20-iodo-9-oxol 3-trans-prostenoate A stirred mixture of 30 g. of ethyl 20-chloro-9-oxol3-trans-prostenoate (Example 48), 25 g. of sodium iodide and 225 ml. of acetone is refluxed for 13 hours. The reaction mixture is concentrated, diluted with water, and extracted with ether. The extract is washed with saturated sodium chloride, dried, and evaporated to give an oil.

EXAMPLES 97-107 Treatment of the corresponding 20- chloroprostenoate or 20-chloro-17,18,19-trinorprostenoate with sodium iodie in acetone by the procedure of Example 95 provides the 20-iodo derivatives of Table V below.

TABLE V Starting 20- Chloro Deriva- Exumple tive of Example Product 97 57 ethyl ZO-rodo-Q-oxo-6,7-dinorl B-transprostcnoate Starting 20- Chloro Den'vative of Example Example Product 98 60 ethyl 20-iodo-9-oxo-6,7, l 7, l 8, l9-

pentanorl 3-trans-prostenoate ethyl 20-iodo-9-oxo-3,4,5,6,7, l 7,- l 8, l9- octanorl 3-trans-prostenoate ethyl 20-iodo-9-oxo-5.6,7-trinorl 3- trans-prostenoate ethyl 20-iodo-9-oxo-7a,7b-dihomol7, 1 8, l9-trinorl S-transprostenoate ethyl 20-iodo-9-oxol Oa-homol 3-transprostenoate ethyl 20-iodo-9-oxol0a-homol7,- 1 8, l 9-trinorl 3-trans-prostenoate ethyl 20-iodo-9-oxol0a-homo-5 ,6,- 7,17,18, l9-hexanor-l 3-transprostenoate ethyl 20-iodo-9-oxol0a-homo-7-norl 3- trans-prostenoate ethyl 20-iodo-9-oxo-7a, l Oa-dihomo- 17, l 8, l 9-trinorl 3-transprostenoate I07 91 ethyl 20-iodo-9-oxo-7a, l Oa-dihomol 3- trans-prostenoate EXAMPLE 108 Preparation of ethyl 9-oxol 8-thial 3-trans-prostenoate To 6.0 ml. of a stirred, ice-cold solution of 0.5M 5- ethylisothiouronium iodide in 10:1 ethanolzwater is added 264 mg. of sodium hydroxide dissolved in 2.0 ml. of ethanol and 4.0 ml. of water. The mixture is stirred under nitrogen at ambient temperature for 15 min. and then cooled in the ice bath while a solution of ethyl. 20- iodo-9-oxol 7, l 8, l 9-trinorl 3-trans-prostenoate (434 mg.) (Example 95) in 3 ml. of ethanol is added. The reaction mixture is stirred successively at 0 for 15 min., at ambient temperature for 15 min., and at 40 for 5 min. The mixture is diluted with water and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated. The crude product is purified by chromatography on silica gel to give an oil, IR 1740 cm (ester and ketone carbonyls) and 967 cm (trans vinyl group); NMR (CCl 82.47 ppm (multiplet, methylenethE-J groups).

EXAMPLES 109-1 14 Treatment according to the procedure of Example 108, of the various 20-iodo-l7,l8,l9-trinor-transprostenoates of Table VI (below) with sodium ethyl mercaptide (prepared in situ as in Example 108) is productive of the various l8-thiaprostenoates of the Table. 

1. THE PROCESS OF PREPARING COMPOUNDS OF FORMULA:
 2. The process according to claim 1 wherein n is 1, R is -(CH2)5CH3, Z is -(CH2)6-, and R'' is methyl.
 3. The process according to claim 1 wherein n is 1, R is
 4. The process according to claim 1 wherein n is 1, R is -CH2CH2CH(CH3)2, Z is -(CH2)6-, and R'' is methyl.
 5. The process according to claim 1 wherein n is 1, R is CH2CH2CH2Cl, Z is -(CH2)6-, and R'' is methyl.
 6. The process according to claim 1 wherein n is 1, R is (CH2)6-Cl, Z is -(CH2)6-, and R'' is methyl.
 7. The process according to claim 1 wherein n is 1, R is -(CH2)5CH3, Z is -(CH2)4-C(CH3)2-CH2-, and R'' is methyl.
 8. The process according to claim 1 wherein n is 2, R is -(CH2)5CH3, Z is -(CH2)6-, and R'' is methyl.
 9. The process according to claim 1 wherein n is 1, R is -(CH2)5CH3, Z is -(CH2)4-O-CH2-, and R'' is methyl.
 10. The process according to claim 1 wherein n is 1, R is -(CH2)5CH2, Z is -(CH2)4-S-CH2-, and R'' is methyl. 